Tosylate salt of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4, 10-dihydro-3H-2,3,4,9-tetrabenzo[f]azulene-9-carbonyl)-2-fluorobenzylamide

ABSTRACT

The invention provides cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate, pharmaceutical compositions containing it, and its use in therapy.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is the National Stage of International Application No. PCT/GB2011/000381, filed Mar. 18, 2011, which claims the benefit of Great Britain Application No. 1004677.9, filed Mar. 19, 2010, and U.S. Provisional Application No. 61/315,468, filed Mar. 19, 2010, the disclosures of which are incorporated herein by reference in their entireties.

The present invention relates to a salt of a vasopressin V_(1a) antagonist, a pharmaceutical composition containing it and its use in therapy.

The neurophyseal hormones vasopressin (VP) and oxytocin (OT) are cyclic nonapeptides secreted by the posterior pituitary gland.

Three subtypes of the VP receptor are known and these are designated the V_(1a), V_(1b), and V₂ receptors. Only one OT receptor has so far been well characterised.

Vasopressin acts on the blood vessels, where it is a potent vasoconstrictor, and on the kidneys, where it promotes water reuptake leading to an antidiuretic effect.

The V_(1a), V_(1b) and V₂, as well as the OT receptors, are members of the super-family of seven transmembrane receptors known as G-protein coupled receptors. The V_(1a) receptor mediates phospholipase C activation and intracellular calcium mobilisation. Localisation of the receptors includes blood platelets, blood vessels, hepatocytes, brain and uterus-cervix. Thus a V_(1a) antagonist may have effects on any or all of these tissues. For example, selective V_(1a) antagonists have been cited as having clinical utility in dysmenorrhoea, pre-term labour, hypertension, Raynaud's disease, brain oedema, motion sickness, hyperlipemia, small cell lung cancer, depression, anxiety, hyponatremia, liver cirrhosis and congestive heart failure.

With respect to dysmenorrhoea it has been proposed that myometrial activity is markedly increased in women with dysmenorrhoea during menstruation. It is proposed that the myometrial ischemia caused by increased uterine contractility might explain the menstrual pain. Furthermore, on the first day of menstruation, higher plasma concentrations of vasopressin have been measured in dysmenorroeic women than in controls.

In healthy women without dysmenorrhoea, intravenous infusion of lysine-vasopressin resulted in decreased uterine blood flow, increased uterine contractility and slight to moderate dysmenorrhoea-like pain, these effects being inhibited by a selective human V_(1a) receptor antagonist (Bossmar, T. et al., British Journal of Obstetrics and Gynaecology (1997 April), 104(4), 471-7). Also, it is known that vasopressin contracts human uterine arteries in a dose-dependent and V_(1a)-mediated fashion.

The above evidence suggests that a V_(1a) antagonist would be an appropriate and effective treatment for dysmenorrhoea (primary dysmenorrhoea and/or secondary dysmenorrhoea). Further evidence is taken from the clinical study carried out on the selective V_(1a) antagonist SR49059 (“Effect of SR49059, an orally active V_(1a) vasopressin receptor antagonist, in the prevention of dysmenorrhea”. Brouard, R. et al., British Journal of Obstetrics and Gynaecology (2000), 107(5), 614-619). It was found that there was a dose-related decrease in pain and a dose-related decrease in the amount of additional pain-killer taken compared to patients taking placebo.

International Patent Application WO 03/016316 A1, published 27 Feb. 2003, discloses a number of compounds which are claimed to be oxytocin agonists and to find use in the treatment of male erectile dysfunction. No V_(1a) antagonist activity is reported. European Patent Application EP 1 449 844 A1, published 25 Aug. 2004, discloses a number of compounds which are claimed to be V_(1a) antagonists and to find use in the treatment of primary dysmenorrhoea.

In the manufacture of pharmaceutical formulations, it is important that the active compound is in a form in which it can be conveniently handled and processed in order to obtain a commercially viable manufacturing process. Accordingly, the chemical stability and the physical stability of the active compound are important factors. The active compound, and formulations containing it, must be capable of being effectively stored over appreciable periods of time, without exhibiting any significant change in the physico-chemical characteristics (e.g. chemical composition, density, hygroscopicity and solubility) of the active compound.

Furthermore, if the active compound is to be incorporated into a dosage form for oral administration, such as a tablet, it is desirable that the active compound be readily micronised to yield a powder with good flow properties to aid manufacture. Moreover, it is desirable that the active compound be soluble to allow for faster and increased absorption of the active compound following administration.

It is known that manufacturing a particular physical form (or polymorph), such as a salt form, of a pharmaceutical ingredient can affect many aspects of its solid state properties and may offer advantages in aspects of solubility, dissolution rate, chemical stability, mechanical properties, technical feasibility, processability, pharmacokinetics and bioavailability. Some of these are described in “Handbook of Pharmaceutical Salts; Properties, Selection and Use”, P. Heinrich Stahl, Camille G. Wermuth (Eds.) (Verlag Helvetica Chimica Acta, Zurich). Methods of manufacturing solid-state forms are described in “Practical Process Research and Development”, Neal G. Anderson (Academic Press, San Diego) and “Polymorphism: In the Pharmaceutical Industry”, Rolf Hilfiker (Ed) (Wiley VCH). Polymorphism in pharmaceutical crystals is described in Byrn (Byrn, S. R., Pfeiffer, R. R., Stowell, J. G., “Solid-State Chemistry of Drugs”, SSCI Inc., West Lafayette, Ind., 1999), Brittain, H. G., “Polymorphism in Pharmaceutical Solids”, Marcel Dekker, Inc., New York, Basel, 1999) or Bernstein (Bernstein, J., “Polymorphism in Molecular Crystals”, Oxford University Press, 2002).

International Patent Application WO 2006/021213 (PCT/DK2005/000540) describes a novel class of vasopressin antagonists that display high, selective potency at the V_(1a) receptor. One such vasopressin antagonist described in PCT/DK2005/000540 is cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide. The preparation of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide described in PCT/DK2005/000540 yields a solid which is poorly soluble and thus less suitable for oral administration. It has now been found possible to prepare a salt of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide, which has unexpectedly advantageous physico-chemical properties and which may be suitable for use in a formulation for oral administration. In particular, the salt form of the present invention was unexpectedly found to be 8× more soluble in water than known free base of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide. Moreover, when tested in a rat model of oral availability, significant improvements in plasma exposure were observed following dosing with the salt of the present invention. In contrast, the known free base was only minimally absorbed when tested in the same model.

Thus, in accordance with the present invention, there is provided a salt which is a tosylate (para-toluenesulphonate) salt of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide. In the present application this salt may be referred to as the ‘tosylate salt’.

The salt of the present invention is herein referred to as cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate. The name cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide denotes the structure depicted in FIG. A.

The present invention encompasses solvates (e.g. hydrates) of the tosylate salt.

Seven different physical forms of the tosylate salt of the present invention have been isolated and characterised to date (Form 1, Form 2, Form 3, Form 4, Form 5, Form 6 and Form 7). All seven are forms of the tosylate salt, i.e. cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate.

In the present specification, X-ray powder diffraction peaks (expressed in degrees 2θ) are measured using copper X-rays with a wavelength of 1.5406 Å (alpha1) and 1.5444 Å (alpha2).

Thus, the present invention also provides a physical form (Form 1) of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate, which exhibits at least the following characteristic X-ray powder diffraction peaks (Cu Kα radiation, expressed in degrees 2θ) at approximately:

(1) 8.2, 21.4, 23.3 and 25.8, or

(2) 8.2, 12.2, 21.4, 23.3 and 25.8, or

(3) 8.2, 12.2, 17.2, 21.4, 23.3 and 25.8

The term “approximately” means in this context that there is an uncertainty in the measurements of the degrees 2θ off 0.2 (expressed in degrees 2θ).

The present invention also provides a physical form (Form 1) of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate, having an X-ray powder diffraction pattern comprising specific peaks (expressed in degrees 2θ) at approximately 8.2, 12.2, 17.2, 20.4, 21.4, 23.3, 25.8 and 27.4.

The present invention also provides a physical form (Form 1) of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate, having an X ray powder diffraction pattern which exhibits at least the following characteristic d-space values (Å) of approximately:

(1) 10.73, 4.15, 3.65 and 3.44, or

(2) 10.73, 7.25, 4.15, 3.65 and 3.44, or

(3) 10.73, 7.25, 5.17, 4.15, 3.65 and 3.44

FIG. 1 shows an X-ray powder diffraction pattern of physical Form 1 of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate. The present invention also provides a salt form having an X-ray powder diffraction pattern substantially the same as that shown in FIG. 1.

FIG. 10 shows an IR spectrum of Form 1 of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate. Accordingly, the present invention provides a provides a salt form which is characterised by an IR spectrum having characteristic peaks expressed in cm⁻¹ at approximately 3359, 3281, 3197, 3067, 2926, approx. 1682 (shoulder), 1651, 1573, 1033 and 1009. The term “approximately” means in this context that the cm⁻¹ values can vary, e.g. by up to ±1 cm⁻¹. Additionally, the present invention provides a salt form having an IR spectrum substantially the same as that shown in FIG. 10.

The present invention also provides a physical form (Form 2) of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate, which exhibits at least the following characteristic X-ray powder diffraction peaks (Cu Kα radiation, expressed in degrees 2θ) at approximately:

(1) 7.9, 16.4, 19.3, and 25.1, or

(2) 7.9, 16.4, 19.3, 21.6 and 25.1, or

(3) 7.9, 16.4, 17.8, 19.3, 21.6 and 25.1.

The present invention also provides a physical form (Form 2) of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate, having an X ray powder diffraction pattern comprising specific peaks (expressed in degrees 2θ) at approximately 7.9, 11.7, 16.4, 17.6, 17.8, 19.3, 21.6 and 25.1.

The present invention also provides a physical form (Form 2) of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate, having an X ray powder diffraction pattern which exhibits at least the following characteristic d-space values (Å) of approximately:

(1) 11.22, 5.39, 4.59, and 3.55, or

(2) 11.22, 5.39, 4.59, 4.11 and 3.55, or

(3) 11.22, 5.39, 4.98, 4.59, 4.11 and 3.55.

FIG. 2 shows an X-ray powder diffraction pattern of physical Form 2 of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate. The present invention also provides a salt form having an X-ray powder diffraction pattern substantially the same as that shown in FIG. 2.

The present invention also provides a physical form (Form 3) of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate, which exhibits at least the following characteristic X-ray powder diffraction peaks (Cu Kα radiation, expressed in degrees 2θ) at approximately:

(1) 7.7, 18.6, 24.9 and 25.0, or

(2) 7.7, 18.6, 20.4, 24.9 and 25.0, or

(3) 7.7, 15.8, 18.6, 20.4, 24.9 and 25.0.

The present invention also provides a physical form (Form 3) of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate, having an X ray powder diffraction pattern comprising specific peaks (expressed in degrees 2θ) at approximately 7.7, 11.9, 15.8, 17.6, 18.6, 20.4, 21.0, 23.1, 24.9 and 25.0.

The present invention also provides a physical form (Form 3) of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate, having an X ray powder diffraction pattern which exhibits at least the following characteristic d-space values (Å) of approximately:

(1) 11.52, 4.78, 3.57 and 3.55, or

(2) 11.52, 4.78, 4.36, 3.57 and 3.55, or

(3) 11.52, 5.61, 4.78, 4.36, 3.57 and 3.55.

FIG. 3 shows an X-ray powder diffraction pattern of physical Form 3 of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate. The present invention also provides a salt form having an X-ray powder diffraction pattern substantially the same as that shown in FIG. 3.

The present invention also provides a physical form (Form 4) of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate, which exhibits at least the following characteristic X-ray powder diffraction peaks (Cu Kα radiation, expressed in degrees 2θ) at approximately:

(1) 10.8, 15.4, 18.8 and 24.9, or

(2) 10.8, 15.5, 18.8, 21.3 and 24.9, or

(3) 10.8, 15.5, 18.8, 21.3, 21.6 and 24.9.

The present invention also provides a physical form (Form 4) of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate, having an X ray powder diffraction pattern comprising specific peaks (expressed in degrees 2θ) at approximately 7.8, 10.8, 15.5, 15.6, 17.8, 18.8, 19.3, 20.6, 21.3, 21.6 and 24.9.

The present invention also provides a physical form (Form 4) of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate, having an X ray powder diffraction pattern which exhibits at least the following characteristic d-space values (Å) of approximately:

(1) 8.21, 5.73, 4.72 and 3.58, or

(2) 8.21, 5.73, 4.72, 4.18 and 3.58, or

(3) 8.21, 5.73, 4.72, 4.18, 4.10 and 3.58.

FIG. 4 shows an X-ray powder diffraction pattern of physical Form 4 of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate. The present invention also provides a salt form having an X-ray powder diffraction pattern substantially the same as that shown in FIG. 4.

The present invention also provides a physical form (Form 5) of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate, which exhibits at least the following characteristic X-ray powder diffraction peaks (Cu Kα radiation, expressed in degrees 2θ) at approximately:

(1) 17.8, 20.3, 23.2, and 28.5, or

(2) 7.7, 17.8, 20.3, 23.2, and 28.5, or

(3) 7.7, 17.8, 20.3, 23.2, 28.2 and 28.5.

The present invention also provides a physical form (Form 5) of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate, having an X ray powder diffraction pattern comprising specific peaks (expressed in degrees 2θ) at approximately 7.7, 17.8, 18.8, 20.3, 21.0, 23.2, 24.5, 25.1, 28.2 and 28.5.

The present invention also provides a physical form (Form 5) of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate, having an X ray powder diffraction pattern which exhibits at least the following characteristic d-space values (Å) of approximately:

(1) 4.99, 4.36, 3.84, and 3.13, or

(2) 11.43, 4.99, 4.36, 3.84, and 3.13, or

(3) 11.43, 4.99, 4.36, 3.84, 3.17 and 3.13.

FIG. 5 shows an X-ray powder diffraction pattern of physical Form 5 of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate. The present invention also provides a salt form having an X-ray powder diffraction pattern substantially the same as that shown in FIG. 5.

The present invention also provides a physical form (Form 6) of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate, which exhibits at least the following characteristic X-ray powder diffraction peaks (Cu Kα radiation, expressed in degrees 2θ) at approximately:

(1) 15.5, 18.2, 21.6 and 25.9, or

(2) 15.5, 18.2, 20.1, 21.6 and 25.9, or

(3) 15.5, 18.2, 20.1, 20.8, 21.6 and 25.9.

The present invention also provides a physical form (Form 6) of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate, having an X ray powder diffraction pattern comprising specific peaks (expressed in degrees 2θ) at approximately 7.5, 15.5, 18.2, 20.1, 20.8, 21.6, 27.3 and 25.9.

The present invention also provides a physical form (Form 6) of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate, having an X ray powder diffraction pattern which exhibits at least the following characteristic d-space values (Å) of approximately:

(1) 5.71, 4.88, 4.12 and 3.44, or

(2) 5.71, 4.88, 4.42, 4.12 and 3.44, or

(3) 5.71, 4.88, 4.42, 4.27, 4.12 and 3.44.

FIG. 6 shows an X-ray powder diffraction pattern of physical Form 6 of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate. The present invention also provides a salt form having an X-ray powder diffraction pattern substantially the same as that shown in FIG. 6.

FIG. 11 shows an IR spectrum of Form 6 of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate. Accordingly, the present invention provides a provides a salt form which is characterised by an IR spectrum having characteristic peaks expressed in cm⁻¹ at approximately 1653, 1549, 1497, 1443, 1420, 1382, 1320, 1223, 1149, 1123, 1032, 1008, 931, 811 and 683. The term “approximately” means in this context that the cm⁻¹ values can vary, e.g. by up to ±1 cm⁻. Additionally, the present invention provides a salt form having an IR spectrum substantially the same as that shown in FIG. 11.

The present invention also provides a physical form (Form 7) of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate, which exhibits at least the following characteristic X-ray powder diffraction peaks (Cu Kα radiation, expressed in degrees 2θ) at approximately:

(1) 7.9, 15.8, 21.6 and 32.7, or

(2) 7.9, 15.8, 21.6, 23.5 and 32.7, or

(3) 7.9, 15.8, 20.1, 21.6, 23.5 and 32.7.

The present invention also provides a physical form (Form 7) of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate, having an X ray powder diffraction pattern comprising specific peaks (expressed in degrees 2θ) at approximately 7.9, 15.8, 19.9, 20.1, 20.7, 21.3, 21.6, 23.2, 23.5, 27.0 and 32.7.

The present invention also provides a physical form (Form 7) of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate, having an X ray powder diffraction pattern which exhibits at least the following characteristic d-space values (Å) of approximately:

(1) 11.26, 5.60, 4.11 and 2.74, or

(2) 11.26, 5.60, 4.11, 3.78 and 2.74, or

(3) 11.26, 5.60, 4.41, 4.11, 3.78 and 2.74.

FIG. 7 shows an X-ray powder diffraction pattern of physical Form 7 of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate. The present invention also provides a salt form having an X-ray powder diffraction pattern substantially the same as that shown in FIG. 7.

FIG. 12 shows an IR spectrum of Form 7 of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate. Accordingly, the present invention provides a provides a salt form which is characterised by an IR spectrum having characteristic peaks expressed in cm⁻¹ at approximately 1675, 1656, 1625, 1572, 1500, 1418, 1378, 1298, 1221, 1154, 1123, 1092, 1035, 1011, 935, 890, 866, 813 and 683. The term “approximately” means in this context that the cm⁻¹ values can vary, e.g. by up to ±1 cm⁻¹. Additionally, the present invention provides a salt form having an IR spectrum substantially the same as that shown in FIG. 12.

The tosylate salt of the present invention can exist in both unsolvated and solvated forms. The term ‘solvate’ is used herein to describe a molecular complex comprising the compound of the invention and an amount of one or more pharmaceutically acceptable solvents, for example, ethanol. The term ‘hydrate’ is employed when the solvent is water.

The tosylate salt of the present invention may be prepared as follows: A mixture of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide (prepared by the method described in PCT/DK2005/000540) and para-toluenesulphonic acid are combined in a suitable solvent (e.g. methanol) and stirred at a suitable temperature (e.g. 20 to 25° C.) for a period of time (e.g. 6 to 24 hours). The solvent is then removed (e.g. by rotary evaporation). The dried material may then be suspended in a suitable solvent (e.g. t-butyl methyl ether) and then sonicated for a suitable time (e.g. 2 to 6 hours) at a suitable temperature (e.g. 50 to 70° C.). The solids may then be collected (e.g. by centrifugation) and dried under vacuum to yield cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate in amorphous form.

Physical Form 1 may, for example, be prepared by heating the amorphous form, prepared as described above, in acetone with stirring at approx. 60° C. for approx. 90 minutes. The solids may then be collected (e.g. by centrifugation) and dried under vacuum to yield physical Form 1.

Alternatively, physical Form 1 may be prepared by adding acetonitrile and ethyl acetate to a solution of the amorphous form in toluene/isobutanol, cooling the mixture and then seeding it with crystals of physical Form 1. After further cooling and stirring, the solids were isolated by filtration, washed with ethyl acetate and then dried to yield physical Form 1.

As previously mentioned, the tosylate salt of the present invention has a number of therapeutic applications, particularly in the treatment of diseases or conditions mediated by vasopressin V_(1a).

Accordingly, the present invention provides cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate, or a pharmaceutically acceptable solvate thereof, as hereinbefore defined, for use in therapy.

The present invention also provides for the use of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate, or a pharmaceutically acceptable solvate thereof, as hereinbefore defined, in the manufacture of a medicament for the treatment of a disease or condition mediated by vasopressin V_(1a) receptors.

The present invention also provides cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate, or a pharmaceutically acceptable solvate thereof, as hereinbefore defined, for use in the treatment of a disease or condition mediated by vasopressin V_(1a) receptors.

The present invention also provides a method of treatment of a disease or condition mediated by vasopressin V_(1a) receptors, said method comprising administering to a mammal in need of such treatment a therapeutically effective amount of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate, or a pharmaceutically acceptable solvate thereof, as hereinbefore defined.

In an aspect, the disease or condition mediated by vasopressin V_(1a) receptors is selected from dysmenorrhoea (primary dysmenorrhoea and/or secondary dysmenorrhoea), pre-term labour, hypertension, Raynaud's disease, brain oedema, motion sickness, hyperlipemia, small cell lung cancer, depression, anxiety, hyponatremia, liver cirrhosis and congestive heart failure.

In an aspect, the disease or condition mediated by vasopressin V_(1a) receptors is dysmenorrhoea (primary dysmenorrhoea and/or secondary dysmenorrhoea).

In the context of the present invention, references herein to “treatment” include references to curative, palliative and prophylactic treatment, unless there are specific indications to the contrary. The terms “therapy, “therapeutic” and “therapeutically” should be construed in the same way.

The tosylate salt of the present invention may be administered alone or in combination with one or more other drugs. Generally, it will be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term “excipient” is used herein to describe any ingredient other than the compound(s) of the invention which may impart either a functional (i.e., drug release rate controlling) and/or a non-functional (i.e., processing aid or diluent) characteristic to the formulations. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

Pharmaceutical compositions suitable for the delivery of the tosylate salt of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).

For administration to human patients, the total daily dose of the tosylate salt of the invention is typically in the range 0.01 mg and 1000 mg, or between 0.1 mg and 250 mg, or between 1 mg and 50 mg depending, of course, on the mode of administration. The total daily dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein. These dosages are based on an average human subject having a weight of about 60 kg to 70 kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.

Accordingly, the present invention provides a pharmaceutical composition comprising cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate, or a pharmaceutically acceptable solvate thereof, as hereinbefore defined, and a pharmaceutically acceptable carrier, diluent or excipient.

The pharmaceutical compositions may be administered topically (e.g. to the skin or to the lung and/or airways) in the form, e.g., of creams, solutions, suspensions, heptafluoroalkane (HFA) aerosols and dry powder formulations; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of solutions or suspensions; or by subcutaneous administration; or by rectal administration in the form of suppositories; or transdermally.

In an embodiment of the invention, the active ingredient is administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, and/or buccal, lingual, or sublingual administration by which the compound enters the blood stream directly from the mouth.

Formulations suitable for oral administration include solid plugs, solid microparticulates, semi-solid and liquid (including multiple phases or dispersed systems) such as tablets; soft or hard capsules containing multi- or nano-particulates, liquids, emulsions or powders; lozenges (including liquid-filled); chews; gels; fast dispersing dosage forms; films; ovules; sprays; and buccal/mucoadhesive patches.

Formulations suitable for oral administration may also be designed to deliver the tosylate salt in an immediate release manner or in a rate-sustaining manner, wherein the release profile can be delayed, pulsed, controlled, sustained, or delayed and sustained or modified in such a manner which optimises the therapeutic efficacy of the said tosylate salt. Means to deliver compounds in a rate-sustaining manner are known in the art and include slow release polymers that can be formulated with the said compounds to control their release.

Examples of rate-sustaining polymers include degradable and non-degradable polymers that can be used to release the said compounds by diffusion or a combination of diffusion and polymer erosion. Examples of rate-sustaining polymers include hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, xanthum gum, polymethacrylates, polyethylene oxide and polyethylene glycol.

Liquid (including multiple phases and dispersed systems) formulations include emulsions, suspensions, solutions, syrups and elixirs. Such formulations may be presented as fillers in soft or hard capsules (made, for example, from gelatin or hydroxypropylmethylcellulose) and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.

The tosylate salt of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Liang and Chen, Expert Opinion in Therapeutic Patents, 2001, 11 (6), 981-986.

The formulation of tablets is discussed in Pharmaceutical Dosage Forms: Tablets, Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).

The invention will now be illustrated by the following non-limiting Examples. In the Examples the following Figures are presented:

FIG. 1: X-ray powder diffraction pattern of physical Form 1 of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate.

FIG. 2: X-ray powder diffraction pattern of physical Form 2 of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate.

FIG. 3: X-ray powder diffraction pattern of physical Form 3 of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate.

FIG. 4: X-ray powder diffraction pattern of physical Form 4 of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate.

FIG. 5: X-ray powder diffraction pattern of physical Form 5 of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate.

FIG. 6: X-ray powder diffraction pattern of physical Form 6 of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate.

FIG. 7: X-ray powder diffraction pattern of physical Form 7 of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate.

FIG. 8: X-ray powder diffraction pattern of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide.

FIG. 9: Plasma exposures following oral administration of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide (free base) and cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate (tosylate salt) in 0.5% HPMC (n=4/group)

FIG. 10: Infra-red spectrum of physical Form 1 of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate.

FIG. 11: Infra-red spectrum of physical Form 6 of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate.

FIG. 12: Infra-red spectrum of physical Form 7 of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate.

GENERAL EXPERIMENTAL DETAILS

All reactions were carried out under an atmosphere of nitrogen unless specified otherwise. All solvents and commercial reagents were used as received.

¹H NMR spectra were recorded on a Jeol EX 270 (270 MHz) or Brucker Avance III (400 MHz) spectrometer with reference to deuterium solvent (CDCl₃ unless otherwise stated) and at RT. Molecular ions were obtained using LCMS which was carried out using a Chromolith Speedrod RP-18e column, 50×4.6 mm, with a linear gradient 10% to 90% 0.1% HCO₂H/MeCN into 0.1% HCO₂H/H₂O over 11 min, flow rate 1.5 mL/min. Data was collected using a Thermofinnigan Surveyor MSQ mass spectrometer with electospray ionisation in conjunction with a Thermofinnigan Surveyor LC system.

Chemical names were generated using the Autonom software provided as part of the ISIS Draw package from MDL Information Systems.

Two methods for measuring differential scanning calorimetry (DSC) thermograms were used:—

1) Using a Perkin-Elmer Diamond Differential Scanning calorimeter (equipped with a liquid-nitrogen cooling unit), with aluminium pans and non-hermetic lids. The sample weights varied between 1-2 mg. The procedure was carried out under a flow of helium gas (20 ml/min) and the temperature studied from 20 to 300° C. at a constant rate of temperature increase of 200° C. per minute. Prior to analysis the instrument was temperature and heat-flow calibrated using an indium reference standard. 2) Using a Mettler DSC 12E model with external cooling using a Julabo F 25 circulating bath. The samples are weighed into aluminium crucibles and then sealed with a pin pricked lid. A heating rate of 10° C. per minute was applied and an empty sealed DSC pan was used as the reference.

Two methods of measuring infra-red spectra were used:—

1) Using a Thermo Nicolet Avatar FT-IR spectrometer with Omnic data processing software. A sample of approximately 3 mg was triturated with 300 mg potassium bromide and compressed under vacuum into a pellet on a hydraulic press. The spectrum of the pellet was recorded in the infrared region of the spectrum between 400 cm⁻¹ and 4000 cm⁻¹. 2) Using a Bruker Tensor 27. The spectrum between 550 cm⁻¹ and 4000 cm⁻¹ is recorded.

Ultra-violet spectra were obtained with solutions of test samples in acetonitrile (Far UV grade—190 nm cut-off) using a SpectroMax UV spectrophotometer in quartz cuvettes. A spectrum was generated over 200-600 nm with 1 nm increments at 25° C. The spectrum obtained from the analysis of the cuvette filled with blank acetonitrile was subtracted from that of the test sample.

Accurate mass determination was performed on a Waters LCT premier time of flight (TOF) mass spectrometer, optimised for resolution in W mode positive ion electrospray before a calibration with sodium formate was performed. A solution of reserpine and nifedipine was prepared and infused into the ion source to give molecular ions of between 100 and 250 CPS and a mass spectrum was acquired for 2 minutes in MCA mode. A solution of test sample was then introduced into this flow at a flow-rate and concentration suitable to produce a molecular ion in the same intensity range as the two calibrant ions. Data was acquired for 2 minutes in MCA mode.

X-Ray Powder Diffraction (XRPD) patterns were collected using sample weights of approximately 2-10 mg, which was gently compressed on the XRPD zero background single obliquely cut silica sample holder. The sample was then loaded into a Philips X-Pert MPD diffractometer or a Philips X-Pert PRO diffractometer and analysed using the following experimental conditions:—

Tube anode: Cu

Generator tension: 40 kV

Tube current: 40 mA

Wavelength alpha1: 1.5406 Å

Wavelength alpha2: 1.5444 Å

Start angle [2 θ]: 5

End angle [2 θ]: 50

Time per step: 2.5 seconds (X-Pert MPD) or 31 seconds (X-Pert Pro)

Cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide (Free Base)

The title compound may be prepared by the method described in PCT/DK2005/000540.

The product arising from the method described in PCT/DK2005/000540 may be recrystallised. The title compound (19.75 g, 43.5 mmol) was taken up in refluxing ethanol (250 mL). To the solution was added hot water (500 mL). The solution was allowed to cool slowly without stirring and left to stand at room temperature for 3 days. The resultant suspension was then stirred in an ice bath for 1 hour and the precipitate collected by vacuum filtration. The solid was dried at 55° C. for 6 hours. It was dried further at room temperature in vacuo for 16 hours. Finally it was dried for 24 hours at room temperature, in vacuo, over phosphorous pentoxide to afford fine white needles (yield 18.49 g, 94%).

Melting point (capillary tube) 235-237° C.

Melting point approximately 235° C. (DSC Method 1, onset temperature)

¹H NMR (270 MHz, d₆ DMSO) δ 0.65-0.67 (4H, m), 1.53-1.62 (1H, m), 3.77 (3H, s), 3.93 (1H, d, J=14.6 Hz), 4.23 (2H, d, J=5.4 Hz), 5.62 (1H, d, J=14.6 Hz), 6.71 (1H, d, J=8.4 Hz), 6.84 (1H, d, J=8.4 Hz), 6.92-6.96 (2H, m), 7.09-7.15 (1H, m), 7.20 (1H, s), 7.37 (1H, s), 8.52 (1H, t, J=5.4 Hz), 8.80 (1H, s) ppm.

An XRPD diffractogram of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide is shown in FIG. 8.

Cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate

2.50 g of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide (5.52 mmol) was dissolved in 20 mL of methanol along with 6.4 mL (5.79 mmol) of 0.905M para-toluenesulphonic acid. The solution was stirred and the methanol removed by rotary evaporation. The dry material was suspended in 20 mL of t-butyl methyl ether and sonicated at 60° C. for 4 hours. The sample was centrifuged to separate the solid material from the supernatant and the solid material was dried under vacuum. The sample of tosylate salt so obtained is hereinafter referred to as the amorphous form.

Physical Form 1

Amorphous form (as prepared herein above) was stirred in acetone (100 mL) at 60° C. for 90 minutes. The sample was centrifuged to separate the solid material from the supernatant and the solid material was dried under vacuum. Successful salt formation was confirmed by XRPD and microanalysis.

Microanalysis (1); C 57.37%, H 4.37%, N 11.29%

Microanalysis (2); C 57.48%, H 4.54%, N 11.32%

(Theoretical; C 57.55%, H 4.67%, 11.19%)

Melting point 204° C. (DSC Method 1, onset temperature)

An XRPD spectrum of Form 1 is presented in FIG. 1.

Peak position table: - Pos. Height FWHM d-spacing Rel. Int. [°2Th.] [cts] [°2Th.] [Å] [%] 6.1161 3.34 0.2362 14.43917 0.97 7.943 47.11 0.0787 11.12174 13.71 8.2299 88.19 0.0984 10.73471 25.67 9.3698 3.05 0.0984 9.43122 0.89 10.5529 34.27 0.0787 8.37633 9.98 11.2676 11.95 0.1968 7.84657 3.48 12.1963 55.78 0.2755 7.25109 16.23 12.766 13.36 0.1574 6.92879 3.89 13.6021 10.43 0.059 6.50467 3.04 14.8254 6.53 0.1968 5.97061 1.9 15.3878 25.92 0.0984 5.75362 7.54 15.994 34.13 0.1968 5.5369 9.93 16.4933 44.2 0.059 5.37039 12.86 17.042 70.38 0.059 5.19868 20.48 17.1468 97.28 0.059 5.16715 28.31 17.8394 82.75 0.059 4.96806 24.08 18.603 38.25 0.1574 4.76582 11.13 20.017 66.67 0.059 4.43225 19.4 20.3803 138.83 0.059 4.35405 40.41 20.6727 85.98 0.0787 4.29312 25.02 21.3778 157.97 0.0984 4.15308 45.98 22.286 47.1 0.0984 3.98585 13.71 23.2746 343.58 0.2165 3.81874 100 24.3462 51.85 0.0984 3.65303 15.09 24.9376 18.38 0.1574 3.56772 5.35 25.8448 133.7 0.096 3.4445 38.91 25.9441 116.19 0.0984 3.43155 33.82 26.6827 42.7 0.0984 3.33821 12.43 27.4416 98.17 0.059 3.24759 28.57 27.927 30.81 0.2362 3.19224 8.97 28.7954 11.42 0.2362 3.09791 3.32 29.3851 9.39 0.1574 3.03707 2.73 29.9507 55.11 0.2362 2.981 16.04 31.1679 24.04 0.3149 2.86729 7 32.0789 20.95 0.3149 2.78792 6.1 33.2414 38.6 0.1968 2.69302 11.24 33.8327 11.92 0.2362 2.6473 3.47 34.83 13.75 0.1968 2.57375 4 35.8516 13.35 0.1181 2.50272 3.88 36.4467 11.9 0.3149 2.46321 3.46 37.3372 7.44 0.1968 2.40648 2.16 38.0824 13.03 0.3149 2.36109 3.79 38.8091 15.76 0.2755 2.31853 4.59 39.6495 17.75 0.2362 2.2713 5.17 40.5044 11.09 0.3149 2.22531 3.23 42.0942 34.92 0.0787 2.14487 10.16 43.3899 13.1 0.3936 2.08378 3.81 44.4489 12.18 0.6298 2.03656 3.54 45.9299 11.9 0.7872 1.97428 3.46 47.2866 6.07 0.6298 1.92075 1.77 49.1985 13.44 0.384 1.85049 3.91

Further quantities of Form 1 were prepared as follows:

A solution of para-toluenesulfonic acid monohydrate in iso-butanol was added to a solution of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide in toluene/iso-butanol. Acetonitrile and ethyl acetate were added. The solution was allowed to cool and seeded with crystals of the title compound (as prepared herein above). After further cooling and stirring, the product was isolated by filtration, washed with ethyl acetate and then dried.

¹H NMR (400 MHz, d₆ DMSO (80 mg/mL)) δ 0.63-0.65 (4H, m), 1.60-1.66 (1H, m), 2.32 (3H, s), 3.92 (3H, s), 4.02 (1H, d, J=14.5 Hz), 4.26 (2H, d, J=5.8 Hz), 5.72 (1H, d, J=14.5 Hz), 6.86 (1H, dd, J=2.1, 8.5 Hz), 6.94 (1H, d, J=8.5 Hz), 7.00-7.04 (2H, m), 7.14-7.18 (3H, m), 7.48 (1H, d, J=2.1 Hz), 7.55 (2H, d, J=8.0 Hz), 7.86 (1H, s), 8.56 (1H, t, J=5.8 Hz), 9.45 (1H, s), 10.71 (1H, brs) ppm.

¹³C NMR (400 MHz, d₆ DMSO (80 mg/mL)) δ 6.35, 13.42, 20.64, 35.00, 35.53, 42.34, 102.78, 114.09, 119.72, 122.01, 123.35, 125.42, 127.92, 128.16, 128.79, 131.28, 131.94, 132.42, 133.11, 136.24, 138.04, 141.72, 144.96, 157.69, 160.12, 166.73, 172.79 ppm.

Infra-red spectroscopy, frequencies consist of at least wavelengths approximately 3359, 3281, 3197, 3067, 2926, approx. 1682 (shoulder), 1651, 1573, 1033, 1009 cm⁻¹. The term “approximately” means in this context that the cm⁻¹ values can vary, e.g. by up to ±1 cm⁻¹. The spectrum is presented in FIG. 10.

Ultra violet absorptions (10 μM) show absorption maxima at wavelengths 223 and 277 nm.

Accurate mass spectrometry; 454.1446 [M+H]⁺ (1.97 ppm error) and 476.1266 [M+Na]⁺ (0.29 ppm error).

LCMS: m/z=454.14, 456.10 (MH⁺), RT=6.14 min. Consistent with natural abundance of chlorine isotopes ³⁵Cl and ³⁷Cl.

Physical Forms 2-4

In general, the tosylate salt (50 mg) was dissolved or slurried in a solvent/anti-solvent mix and shaken for 24 hours at −20° C. Details of the solvents are shown in the Table below. Resulting solids were isolated by removing the supernatant and drying the solids under vacuum. In experiments where precipitation was not observed, the solutions were concentrated by rotary evaporation to yield a precipitate which was filtered and dried under vacuum.

All samples were characterised by DSC (Method. 1, see data in Table below).

Assigned DSC approximate Crystallisation Conditions Form onset temperature Ethanol:Ethyl acetate (20:80) Form 2 204° C. Acetone:Acetonitrile (80:20) Form 3 179° C. Acetone:Octanol (60:40) Form 3 179° C. Acetone:Dioxane (40:60) Form 4 170° C.

All samples were analysed by XRPD (see FIGS. 2 to 4).

Peak Position Tables:

Tosylate Salt (Form 2)

Pos. Height FWHM d-spacing Rel. Int. Tip width [°2Th.] [cts] [°2Th.] [Å] [%] [°2Th.] 5.5852 26.09 0.0590 15.81050 4.41 0.0708 6.7260 3.23 0.3149 13.13123 0.55 0.3779 7.8725 435.64 0.0984 11.22122 73.61 0.1181 8.2567 48.03 0.1181 10.69994 8.12 0.1417 9.1096 2.72 0.0787 9.69998 0.46 0.0945 10.8640 49.00 0.0590 8.13717 8.28 0.0708 11.0557 45.04 0.0590 7.99648 7.61 0.0708 11.2936 26.91 0.0394 7.82860 4.55 0.0472 11.6469 100.25 0.0984 7.59190 16.94 0.1181 11.8443 76.32 0.0984 7.46578 12.90 0.1181 12.3887 18.44 0.2362 7.13894 3.12 0.2834 13.6633 66.80 0.1574 6.47567 11.29 0.1889 15.1063 106.95 0.0590 5.86021 18.07 0.0708 15.2603 113.05 0.0787 5.80142 19.10 0.0945 16.4429 186.81 0.0787 5.38672 31.57 0.0945 16.5987 185.42 0.1181 5.33651 31.33 0.1417 17.6146 240.69 0.0984 5.03097 40.67 0.1181 17.8134 341.65 0.0787 4.97526 57.73 0.0945 18.0458 45.15 0.0787 4.91171 7.63 0.0945 18.5284 10.28 0.0787 4.78486 1.74 0.0945 19.3406 591.82 0.2362 4.58570 100.00 0.2834 20.2575 178.75 0.1440 4.38016 30.20 0.1728 21.2995 166.08 0.1200 4.16818 28.06 0.1440 21.6122 279.63 0.0960 4.10857 47.25 0.1152 22.6862 85.03 0.2400 3.91643 14.37 0.2880 23.2749 105.07 0.0960 3.81869 17.75 0.1152 23.6400 58.45 0.1920 3.76053 9.88 0.2304 24.3041 42.43 0.0960 3.65927 7.17 0.1152 24.5957 133.24 0.1200 3.61653 22.51 0.1440 25.0710 183.05 0.1680 3.54903 30.93 0.2016 25.5397 52.98 0.1440 3.48495 8.95 0.1728 26.0123 220.20 0.2160 3.42270 37.21 0.2592 26.2799 102.99 0.0720 3.38846 17.40 0.0864 26.7498 185.69 0.0960 3.32999 31.38 0.1152 27.1230 131.23 0.1200 3.28502 22.17 0.1440 27.9007 66.18 0.0720 3.19519 11.18 0.0864 28.5086 138.06 0.1200 3.12842 23.33 0.1440 28.9197 71.48 0.1440 3.08488 12.08 0.1728 29.9362 45.33 0.1200 2.98241 7.66 0.1440 30.4258 69.73 0.0720 2.93552 11.78 0.0864 30.8373 38.85 0.1920 2.89728 6.57 0.2304 31.2658 54.21 0.1920 2.85854 9.16 0.2304 31.5814 35.21 0.1440 2.83069 5.95 0.1728 32.1715 32.30 0.1200 2.78010 5.46 0.1440 32.8002 52.33 0.2400 2.72824 8.84 0.2880 33.1579 126.94 0.0960 2.69962 21.45 0.1152 34.0294 14.13 0.2880 2.63245 2.39 0.3456 34.6522 19.52 0.1440 2.58654 3.30 0.1728 35.8417 67.86 0.3840 2.50338 11.47 0.4608 36.5011 43.80 0.1920 2.45966 7.40 0.2304 37.6759 43.99 0.1440 2.38562 7.43 0.1728 38.2690 91.76 0.2400 2.35000 15.50 0.2880 39.8063 79.06 0.1440 2.26271 13.36 0.1728 40.7873 30.36 0.1920 2.21053 5.13 0.2304 41.5470 19.10 0.2400 2.17185 3.23 0.2880 42.7075 16.08 0.3840 2.11548 2.72 0.4608 43.9531 83.43 0.0720 2.05837 14.10 0.0864 44.9161 23.18 0.2880 2.01645 3.92 0.3456 45.5644 33.46 0.2400 1.98926 5.65 0.2880 45.9890 31.91 0.2400 1.97187 5.39 0.2880 46.6160 33.76 0.5760 1.94680 5.70 0.6912 46.8650 37.96 0.1440 1.93704 6.41 0.1728 47.6557 49.06 0.3840 1.90673 8.29 0.4608 48.1107 47.74 0.1920 1.88975 8.07 0.2304 Tosylate Salt (Form 3)

Pos. Height FWHM d-spacing Rel. Int. [°2Th.] [cts] [°2Th.] [Å] [%] 5.5427 19.32 0.1181 15.93150 4.50 7.6664 213.40 0.1378 11.52243 49.76 10.8685 43.47 0.0984 8.13378 10.14 11.3118 23.69 0.0590 7.81601 5.52 11.8783 71.63 0.1574 7.44451 16.70 12.4856 28.06 0.1181 7.08374 6.54 13.3728 17.56 0.1181 6.61569 4.10 14.9932 79.91 0.0787 5.90417 18.63 15.3422 103.94 0.0590 5.77062 24.24 15.7859 160.13 0.0984 5.60942 37.34 15.8954 112.39 0.0787 5.57101 26.20 16.6305 126.20 0.1181 5.32637 29.43 17.2303 105.21 0.0787 5.14229 24.53 17.5359 160.07 0.1181 5.05336 37.32 17.8852 87.61 0.1181 4.95546 20.43 18.5645 197.35 0.1378 4.77563 46.02 19.1490 94.84 0.0960 4.63116 22.11 19.2080 117.20 0.0590 4.61707 27.33 19.6616 14.04 0.1968 4.51156 3.27 20.3608 184.55 0.1574 4.35818 43.03 21.0420 221.33 0.0984 4.21860 51.61 21.7704 167.69 0.0984 4.07907 39.10 22.1229 75.35 0.0787 4.01487 17.57 22.4595 148.99 0.0787 3.95546 34.74 23.0876 156.55 0.0984 3.84924 36.50 23.7110 54.07 0.0787 3.74943 12.61 24.1983 37.32 0.2362 3.67502 8.70 24.9297 311.69 0.1200 3.56884 72.68 25.0295 428.88 0.1378 3.55483 100.00 26.0518 168.55 0.1378 3.41761 39.30 26.8205 77.14 0.3149 3.32138 17.99 27.5978 37.37 0.1968 3.22957 8.71 28.0013 46.02 0.1574 3.18393 10.73 28.4970 133.63 0.1968 3.12966 31.16 28.7856 43.70 0.0787 3.09894 10.19 29.6274 18.50 0.1574 3.01278 4.31 30.9028 28.47 0.1968 2.89129 6.64 31.8038 42.81 0.1968 2.81140 9.98 32.9329 47.70 0.1574 2.71755 11.12 33.9440 12.89 0.1968 2.63888 3.00 34.7539 37.92 0.1968 2.57921 8.84 36.1237 20.57 0.0984 2.48449 4.80 36.9574 18.49 0.2362 2.43034 4.31 37.6271 25.80 0.1574 2.38860 6.02 38.1091 30.58 0.1968 2.35949 7.13 38.6076 10.76 0.1968 2.33016 2.51 39.8057 16.11 0.9446 2.26275 3.76 40.8286 12.41 0.0984 2.20839 2.89 41.1459 7.04 0.6298 2.19209 1.64 42.5236 30.34 0.1968 2.12420 7.07 43.9909 27.09 0.2362 2.05669 6.32 45.1491 10.17 0.1574 2.00659 2.37 45.7194 28.71 0.2362 1.98288 6.69 46.3312 21.00 0.1968 1.95810 4.90 48.2114 14.83 0.1920 1.88604 3.46 Tosylate Salt (Form 4)

Pos. Height FWHM d-spacing Rel. Int. [°2Th.] [cts] [°2Th.] [Å] [%] 7.7464 174.31 0.1181 11.40356 49.85 10.7629 100.88 0.1181 8.21333 28.85 11.1226 38.60 0.0590 7.94855 11.04 11.7735 51.39 0.1181 7.51053 14.70 12.4248 7.69 0.1574 7.11828 2.20 13.1511 17.41 0.1181 6.72672 4.98 14.6024 45.10 0.1968 6.06127 12.90 15.4450 129.55 0.0787 5.73245 37.05 15.6113 135.32 0.0590 5.67174 38.70 15.9392 96.72 0.1181 5.55582 27.66 16.7372 72.73 0.0787 5.29267 20.80 16.8295 79.44 0.0590 5.26386 22.72 17.1153 68.92 0.1574 5.17657 19.71 17.7858 226.01 0.1378 4.98293 64.64 18.0639 62.60 0.1181 4.90681 17.90 18.8021 241.42 0.1181 4.71580 69.05 19.2754 174.67 0.1378 4.60107 49.95 19.9134 24.52 0.1181 4.45507 7.01 20.5634 210.44 0.1574 4.31569 60.19 20.8227 187.80 0.1378 4.26252 53.71 21.2636 201.68 0.1181 4.17514 57.68 21.6334 213.61 0.1968 4.10459 61.09 22.2111 117.30 0.0984 3.99912 33.55 22.6910 32.27 0.0394 3.91562 9.23 23.4259 182.97 0.0984 3.79442 52.33 23.8408 76.08 0.1574 3.72932 21.76 24.2765 173.88 0.1378 3.66337 49.73 24.8450 349.65 0.1181 3.58081 100.00 25.5485 38.62 0.1574 3.48378 11.05 25.6937 53.02 0.0590 3.46441 15.16 26.3244 171.38 0.0590 3.38283 49.01 26.8167 71.60 0.1968 3.32183 20.48 27.2923 64.28 0.1574 3.26502 18.39 27.5244 26.77 0.0984 3.23802 7.66 27.8961 70.69 0.2362 3.19570 20.22 28.3790 180.78 0.1771 3.14241 51.70 29.0096 44.09 0.0787 3.07553 12.61 29.8649 48.54 0.1574 2.98936 13.88 30.2431 39.86 0.0590 2.95284 11.40 30.7704 19.29 0.0787 2.90342 5.52 31.1063 20.06 0.1181 2.87283 5.74 31.5035 17.78 0.1574 2.83751 5.08 31.8259 41.68 0.0590 2.80950 11.92 32.1507 45.97 0.1968 2.78185 13.15 32.5549 18.36 0.1181 2.74824 5.25 33.2454 25.53 0.1574 2.69271 7.30 33.9996 29.07 0.1968 2.63468 8.31 34.3994 30.21 0.1574 2.60497 8.64 34.7436 17.87 0.1968 2.57995 5.11 35.4357 32.82 0.2755 2.53113 9.39 36.4511 13.59 0.2362 2.46292 3.89 37.0563 36.56 0.1968 2.42408 10.46 38.1537 37.61 0.1968 2.35684 10.76 38.5425 24.30 0.1968 2.33395 6.95 39.1407 9.10 0.1968 2.29965 2.60 40.3633 20.73 0.3149 2.23277 5.93 40.8758 17.67 0.1968 2.20595 5.05 41.7350 9.28 0.3936 2.16250 2.65 43.2701 41.85 0.0787 2.08927 11.97 44.0503 19.05 0.1574 2.05406 5.45 44.6658 27.99 0.0984 2.02717 8.01 46.4165 24.71 0.1968 1.95471 7.07 47.7596 28.50 0.0590 1.90282 8.15 48.6633 16.95 0.1920 1.86958 4.85

NMR data showed that all samples were present as the salt and that the stoichiometry was 1:1. Microanalysis data (C, H, N) also confirmed formation of salt (see Table below).

Theoretical Theoretical Theoretical Experimental Experimental Experimental Sample Carbon Hydrogen Nitrogen Carbon Hydrogen Nitrogen Name % % % % % % Form 2 57.55 4.67 11.19 57.65 4.57 10.89 57.55 4.40 11.01 Form 3 57.55 4.67 11.19 57.53 4.68 10.89 57.58 4.59 10.79 Form 4 57.55 4.67 11.19 57.88 4.42 10.90 57.91 4.45 10.80 Physical Form 5

A solution of the tosylate salt was prepared (100 mg/ml) in methanol. An aliquot was were dispensed into a 96-well plate and 1 ml of tetrahydrofuran (THF) was added to afford a precipitate. The excess solvent was decanted and the crystals dried under vacuum for 24 hours.

The sample was analysed by XRPD (see FIG. 5).

Peak position table: Pos. Height FWHM d-spacing Rel. Int. [°2Th.] [cts] [°2Th.] [Å] [%] 7.3122 14.69 0.1440 12.07977 1.28 7.7267 199.08 0.0960 11.43258 17.38 10.6654 37.31 0.1200 8.28825 3.26 10.9989 16.81 0.0960 8.03768 1.47 11.6970 56.50 0.1200 7.55951 4.93 13.1713 13.19 0.1440 6.71648 1.15 14.8084 33.32 0.0960 5.97740 2.91 15.2775 21.64 0.1440 5.79490 1.89 15.8331 75.68 0.1920 5.59279 6.61 16.4901 42.86 0.1200 5.37140 3.74 17.0849 44.58 0.1440 5.18574 3.89 17.5974 112.11 0.0720 5.03585 9.79 17.7682 326.91 0.0960 4.98782 28.53 17.9881 57.47 0.0720 4.92732 5.02 18.7855 245.04 0.0720 4.71994 21.39 19.1215 176.17 0.0720 4.63776 15.38 20.1045 32.55 0.0720 4.41316 2.84 20.3338 238.61 0.1440 4.36390 20.83 21.0330 450.80 0.0960 4.22039 39.35 21.3713 130.40 0.0960 4.15434 11.38 21.8860 102.96 0.0960 4.05778 8.99 22.2900 53.55 0.3840 3.98514 4.67 22.5102 88.18 0.0720 3.94666 7.70 23.1729 821.45 0.0960 3.83526 71.70 23.7535 19.03 0.1440 3.74283 1.66 24.4843 602.56 0.0960 3.63273 52.59 25.0518 893.76 0.0720 3.55172 78.01 25.3986 48.62 0.1440 3.50400 4.24 26.0294 322.02 0.0720 3.42049 28.11 26.1248 204.21 0.0720 3.40822 17.82 26.3520 34.60 0.1440 3.37934 3.02 26.8291 157.69 0.0960 3.32033 13.76 27.0090 43.52 0.1440 3.29861 3.80 27.2457 48.33 0.0720 3.27050 4.22 27.6954 38.75 0.2880 3.21840 3.38 28.1703 619.57 0.0960 3.16522 54.08 28.4843 1145.67 0.0720 3.13104 100.00 28.7755 39.00 0.1200 3.10001 3.40 29.0781 14.63 0.0960 3.06844 1.28 29.9202 28.82 0.1440 2.98396 2.52 30.2441 67.61 0.0720 2.95274 5.90 31.7100 19.95 0.1920 2.81950 1.74 32.1902 32.32 0.2400 2.77853 2.82 33.1033 65.99 0.1440 2.70394 5.76 33.4701 10.82 0.1200 2.67515 0.94 33.8603 15.44 0.0720 2.64521 1.35 34.5200 29.37 0.0720 2.59615 2.56 34.9430 6.91 0.0720 2.56569 0.60 35.2950 51.56 0.0720 2.54090 4.50 35.7611 68.67 0.1680 2.50884 5.99 35.9963 18.91 0.0720 2.49299 1.65 36.5789 47.00 0.0960 2.45460 4.10 36.9113 45.66 0.1200 2.43326 3.99 37.3909 40.57 0.0960 2.40315 3.54 37.6249 200.47 0.0720 2.38874 17.50 38.0512 17.03 0.0720 2.36295 1.49 38.6741 12.69 0.1440 2.32631 1.11 39.1034 16.38 0.1920 2.30175 1.43 39.8265 20.21 0.1200 2.26162 1.76 40.5267 13.55 0.0720 2.22414 1.18 41.2363 16.75 0.1200 2.18749 1.46 42.4350 6.36 0.0960 2.12843 0.55 42.8444 30.67 0.1200 2.10904 2.68 43.6166 10.45 0.1440 2.07347 0.91 44.1443 7.70 0.1680 2.04990 0.67 44.3130 9.78 0.0720 2.04249 0.85 44.5519 13.83 0.0960 2.03209 1.21 44.7737 3.56 0.0960 2.02253 0.31 45.0260 27.09 0.0720 2.01179 2.36 45.2231 49.65 0.0720 2.00348 4.33 45.3734 7.16 0.0960 1.99719 0.62 45.8825 20.30 0.1440 1.97620 1.77 46.4636 23.62 0.1440 1.95283 2.06 47.3681 45.09 0.0720 1.91763 3.94 47.9143 10.89 0.1440 1.89704 0.95 48.2134 22.67 0.1440 1.88597 1.98 48.6051 5.32 0.0960 1.87168 0.46

Melting point approximately 183° C./204° C. (DSC Method 1, onset temperature). It is suspected that initially the sample is a THF solvate which desolvates on heating to yield a mixture of two polymorphic forms.

Microanalysis (1); C 57.56%, H 4.63%, N 10.81%

Microanalysis (2); C 57.48%, H 4.82%, N 10.78%

(Theoretical; C 57.55%, H 4.67%, 11.19%)

Physical Form 6

Cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide (72.50 g) was placed in a reactor vessel. To this was added 300 mL of an 8.1% aqueous methyl ethyl ketone (MEK) solution and the mixture stirred and warmed to 25° C. Stirring was maintained at 25° C. for approximately 15 minutes. To this was added a solution of para-toluenesulfonic acid monohydrate (30.38 g) in MEK (200 mL) in one portion. The mixture was stirred at 20-25° C. for 5 hours at which point it was a homogeneous solution. The solution was left overnight at 20-25° C. to give a precipitate. 250 mL of 6% aqueous MEK was added. The mixture cleared somewhat and after stirring for 30 minutes another 250 mL of 6% MEK was added at which point the mixture became a coloured solution. The solution was cooled to 40° C. Meanwhile a seeding suspension of the title compound (1 g; Form 1, prepared using the method described herein above) in 10 mL MEK (cone 100 mg ml⁻¹) was prepared.

Once the vessel had been stable at 40° C. for 30 minutes the seeding suspension was added. The seeds were observed to persist and then 2000 mL of MEK was added over a period of 3 minutes and 5 seconds. The temperature of the mixture dropped to 30.0° C. The jacket was maintained at 40° C. for 5 minutes (the vessel warmed back up to 41.8° C. before cooling) and then the jacket was set to 10° C. The mixture was stirred for 90 minutes at 10° C. Stirring was stopped and the solid material settled rapidly on the bottom. The solid was drained from the vessel and filtered. The vessel and solid were washed with 250 mL of MEK and the solid was air dried. NMR analysis indicated the presence of approximately 0.76 mole equivalents of MEK.

The sample was analysed by XRPD (see FIG. 6).

Peak position table: Pos. Height FWHM d-spacing Rel. Int. [°2Th.] [cts] [°2Th.] [Å] [%] 7.5268 254.83 0.1506 11.74556 16.82 10.6994 168.12 0.1673 8.26885 12.33 11.0944 69.45 0.09 7.97532 1.85 11.6702 139.88 0.184 7.58304 11.28 12.3022 67.46 0.2007 7.1949 5.94 13.0324 42.97 0.09 6.79337 1.15 14.7597 212.14 0.1151 6.002 7.23 15.122 317.65 0.2456 5.859 23.12 15.5145 432.35 0.2342 5.71166 44.39 16.4628 289.31 0.1506 5.3847 19.1 16.8287 305.55 0.1673 5.26844 22.41 17.3235 395.22 0.184 5.11907 31.88 17.7286 293.75 0.184 5.00301 23.7 18.1946 577.32 0.184 4.87591 46.57 18.8746 390.14 0.184 4.70175 31.47 19.4744 192.15 0.008 4.55828 0.46 20.1057 584.8 0.2007 4.41656 51.47 20.7827 675 0.184 4.27417 54.45 21.5675 556.89 0.184 4.12039 44.93 22.0003 499.06 0.2165 4.0403 32.02 22.2831 460.5 0.1506 3.98967 30.39 22.9434 477.47 0.1673 3.87632 35.02 23.9267 183.43 0.2007 3.71919 16.14 24.8662 1239.6 0.184 3.58077 100 25.879 599.78 0.184 3.44288 48.39 26.6163 293.07 0.2676 3.34916 34.39 27.2838 321.58 0.2799 3.26872 26.66 28.3587 323.65 0.1673 3.14723 23.74 29.4387 130.49 0.2007 3.03418 11.48 32.0689 101.83 0.2676 2.79107 11.95 32.7612 87.36 0.2676 2.73366 10.25

Infra-red spectroscopy, frequencies consist of at least wavelengths approximately 1653, 1549, 1497, 1443, 1420, 1382, 1320, 1223, 1149, 1123, 1032, 1008, 931, 811, 683 cm⁻¹. The spectrum is presented in FIG. 11.

Melting point 201° C. (DSC Method 2, onset temperature)

Physical Form 7

The tosylate salt (6 g, 9.6 mmol) was taken up in a mixture of water (0.9 mL) and methyl ethyl ketone (MEK) (14.1 mL) and warmed to 74° C. at a rate of 2° C. per minute. The mixture was maintained at 74° C. for 45 minutes then aliquots of water (0.05 mL per aliquot) were added while stirring until the solid had dissolved. The mixture was cooled to 5° C. at a rate of 0.1° C. per minute and maintained at 5° C. for 5 hours. The mixture was warmed to 20° C. at a rate of 0.1° C. The final composition was a concentration of tosylate salt of 391 mg/mL in a mixture of 8.1% water in MEK. The solid was filtered to afford an off-white solid (yield 3 g, 50%).

The sample was analysed by XRPD (see FIG. 7).

Peak position table: Pos. Height FWHM d-spacing Rel. Int. [°2Th.] [cts] [°2Th.] [Å] [%] 6.1474 105 0.09 14.37777 0.99 6.8148 644.02 0.1338 12.97102 13.33 7.8503 1206.13 0.1506 11.26229 28.08 8.1252 341.77 0.1338 10.88188 7.07 10.6014 111.29 0.09 8.34507 1.05 11.3073 158.97 0.3346 7.82563 8.22 12.1516 169.97 0.3346 7.28372 8.79 12.9644 483.78 0.1673 6.82882 12.51 13.6842 662.54 0.1673 6.47122 17.14 14.2976 152.64 0.2007 6.19491 4.74 15.0887 217.03 0.2007 5.87185 6.74 15.8193 660.93 0.2175 5.60229 22.22 16.3717 501.82 0.2007 5.41448 15.58 17.0471 366.31 0.2175 5.20144 12.32 17.8315 680.12 0.2175 4.97437 22.87 18.4672 938.82 0.1673 4.80454 24.28 19.3201 864.99 0.2342 4.59431 31.32 19.8882 1672.82 0.1338 4.46436 34.61 20.1449 2663.32 0.184 4.40805 75.78 20.7025 1267.07 0.3346 4.29055 65.55 21.2592 987.57 0.2007 4.17944 30.65 21.6178 1365.29 0.1673 4.11092 35.31 22.192 417.94 0.1673 4.00584 10.81 23.1692 1907.55 0.184 3.83905 54.27 23.5444 1390.9 0.1506 3.77871 32.38 23.8075 808.19 0.1673 3.73755 20.9 24.2515 434.92 0.1338 3.67012 9 24.7094 418.2 0.3346 3.60314 21.63 25.5013 761.14 0.184 3.49301 21.66 26.4566 3221.84 0.2007 3.36902 100 26.947 1325.81 0.184 3.30881 37.72 27.3602 726.18 0.2007 3.25977 22.54 29.1332 446.38 0.1506 3.06529 10.39 29.4254 415.87 0.1338 3.03552 8.61 29.9127 285.04 0.2676 2.98716 11.8 30.7424 703.89 0.2007 2.90841 21.85 31.148 607.52 0.1673 2.87146 15.71 32.1517 546.14 0.184 2.78408 15.54 32.6953 720.09 0.184 2.73902 20.49 33.0889 494.23 0.1673 2.70733 12.78 34.8881 93.45 0.5353 2.57172 7.73 36.2086 236.89 0.2007 2.48091 7.35 36.6135 384.94 0.1673 2.4544 9.96 39.6676 184.74 0.2007 2.27219 5.73 40.2478 305.04 0.2007 2.24076 9.47 42.1142 102.96 0.4015 2.14567 6.39 44.381 159.89 0.3011 2.0412 7.44 46.8935 66.01 0.4896 1.93593 6.75

Infra-red spectroscopy, frequencies consist of at least wavelengths approximately 1675, 1656, 1625, 1572, 1500, 1418, 1378, 1298, 1221, 1154, 1123, 1092, 1035, 1011, 935, 890, 866, 813, 683 cm⁻¹. The spectrum is presented in FIG. 12.

Melting point 200° C. (DSC Method 2, onset temperature)

Solubility

A comparison of the thermodynamic solubilities of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide (free base) and cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate (tosylate) was carried out. A spectrophotometric method was used. Standards were prepared in methanol (including a methanol blank) and the absorbance measured at 260 and 270 nm, from which a calibration line was generated for each wavelength. The test compound was incubated with agitation in water at 37° C. for 24 h before removal of non-soluble material by centrifugation. The supernatant was analysed against the calibration lines (after subtraction of the water blank response) and the mean of the determinations at the two wavelengths was reported.

The results were as follows:

Form Solubility (μg/ml) in water Free base 5 Tosylate 40 Oral Availability

The plasma exposure in rats following dosing with the cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate (“Tosylate”) has been examined in comparison with the corresponding free base, cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide (“Free Base”). Suspensions of the Tosylate and Free Base were administered in 0.5% HPMC at 10 mg/kg p.o. Results are shown in FIG. 9. As a suspension, the Free Base is minimally absorbed however the Tosylate reaches a C_(max) of 209 ng/mL and AUC_(last) equals 40204 min·ng/mL.

Biological Activity

The ability of the tosylate salt of the invention to inhibit the vasopressin V_(1a) receptor may be determined using the in vitro functional calcium mobilisation assay (FLIPR) described in PCT/DK2005/000540. This assay measures antagonist activity at a cloned human V_(1a) receptor.

When tested in this assay the tosylate salt of the present invention showed a mean fpKi (Human V1a) of 8.5. 

The invention claimed is:
 1. A solid form of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate which exhibits at least the following characteristic X-ray powder diffraction peaks (Cu Kα radiation, expressed in degrees 2θ) at approximately 8.2, 12.2, 17.2, 21.4, 23.3 and 25.8.
 2. The solid form according to claim 1, having an X-ray powder diffraction pattern substantially the same as that shown in FIG.
 1. 3. The solid form of claim 1, which is characterised by an IR spectrum having characteristic peaks expressed in cm⁻¹ at approximately 3359, 3281, 3197, 3067, 2926, approx. 1682 (shoulder), 1651, 1573, 1033 and
 1009. 4. The solid form according to claim 3 having an infrared spectrum substantially the same as that shown in FIG.
 10. 5. A solid form of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate, which exhibits at least the following characteristic X-ray powder diffraction peaks (Cu Kα radiation, expressed in degrees 2θ) at approximately 7.9, 16.4, 17.8, 19.3, 21.6 and 25.1.
 6. The solid form according to claim 5 having an X-ray powder diffraction pattern substantially the same as that shown in FIG.
 2. 7. A solid form of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate, which exhibits at least the following characteristic X-ray powder diffraction peaks (Cu Kα radiation, expressed in degrees 2θ) at approximately 7.7, 15.8, 18.6, 20.4, 24.9 and 25.0.
 8. The solid form according to claim 7 having an X-ray powder diffraction pattern substantially the same as that shown in FIG.
 3. 9. A solid form of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate, which exhibits at least the following characteristic X-ray powder diffraction peaks (Cu Kα radiation, expressed in degrees 2θ) at approximately 10.8, 15.5, 18.8, 21.3, 21.6 and 24.9.
 10. The solid form according to claim 9 having an X-ray powder diffraction pattern substantially the same as that shown in FIG.
 4. 11. A solid form of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate, which exhibits at least the following characteristic X-ray powder diffraction peaks (Cu Kα radiation, expressed in degrees 2θ) at approximately 7.7, 17.8, 20.3, 23.2, 28.2 and 28.5.
 12. The solid form according to claim 11 having an X-ray powder diffraction pattern substantially the same as that shown in FIG.
 5. 13. A solid form of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate, which exhibits at least the following characteristic X-ray powder diffraction peaks (Cu Kα radiation, expressed in degrees 2θ) at approximately 15.5, 18.2, 20.1, 20.8, 21.6 and 25.9.
 14. The solid form according to claim 13 having an X-ray powder diffraction pattern substantially the same as that shown in FIG.
 6. 15. The solid form of claim 13, which is characterised by an infrared spectrum having characteristic peaks expressed in cm⁻¹ at approximately 1653, 1549, 1497, 1443, 1420, 1382, 1320, 1223, 1149, 1123, 1032, 1008, 931, 811 and
 683. 16. The solid form according to claim 15 having an IR spectrum substantially the same as that shown in FIG.
 11. 17. A solid form of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate, which exhibits at least the following characteristic X-ray powder diffraction peaks (Cu Kα radiation, expressed in degrees 2θ) at approximately 7.9, 15.8, 20.1, 21.6, 23.5 and 32.7.
 18. The solid form according to claim 17 having an X-ray powder diffraction pattern substantially the same as that shown in FIG.
 7. 19. The solid form of claim 17, which is characterised by an infrared spectrum having characteristic peaks expressed in cm⁻¹ at approximately 1675, 1656, 1625, 1572, 1500, 1418, 1378, 1298, 1221, 1154, 1123, 1092, 1035, 1011, 935, 890, 866, 813 and
 683. 20. The solid form according to claim 19 having an IR spectrum substantially the same as that shown in FIG.
 12. 21. A pharmaceutical composition comprising cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate and a pharmaceutically acceptable adjuvant, diluent or carrier, in which the cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate in the composition is the solid form of any one of claims 1, 3, 5, 7, 9, 11, 13, 15, 17, or
 19. 22. A method of treatment of a disease or condition mediated by vasopressin V_(1a) receptors, said method comprising administering to a mammal in need of such treatment a therapeutically effective amount of the solid form of cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide para-toluenesulphonate according to any one of claims 1, 3, 5, 7, 9, 11, 13, 15, 17, or 19, wherein said disease or condition mediated by vasopressin V_(1a) receptors is dysmenorrhoea. 